Long-Term Declines in Physical Fitness and Physical Activity for Individuals With Post-Liver Transplantation Compared to Healthy Controls.
Functional changes are essential determinants of mortality and morbidity in individuals with chronic liver disease. However, there is limited information about whether these changes persist long-term after liver transplantation (LT). We aimed to compare physical fitness, physical activity, balance, kinesiophobia, and fatigue between patients with LT and healthy controls. All participants underwent evaluation with the Senior Fitness Test (SFT) for exercise capacity and physical fitness, the International Physical Activity Questionnaire (IPAQ) for physical activity, the Timed Up-and-Go Test (TUG) and the Berg Balance Scale (BBS) for balance, the Tampa Scale for Kinesiophobia (TSK) for kinesiophobia, and the Fatigue Severity Scale (FSS) and Fatigue Impact Scale (FIS) for fatigue. We studied 16 persons with LT (M age = 40.56, SD = 15.73 years; M time since LT = 66.81, SD = 72.05 months) and 16 control participants (M age = 39.87, SD = 13.98 years). Compared to controls, participants with LT showed significantly poorer performance on the SFT components assessing upper and lower body strength, aerobic endurance, agility, and dynamic balance (p < .001 for all), significantly lower IPAQ physical activity scores (p = .002) and BBS score (p = .017), and significantly higher TUG time (p < .001) and TSK, FSS, and FIS scores (p = .001, p = .001, and p = .004, respectively). Individuals with post-LT had lower exercise capacity, physical fitness, balance, and physical activity, and higher kinesiophobia and fatigue levels in the long-term compared to their peers. Future studies should focus on frailty in individuals in the long term after LT.


Toll-like receptors in neurodegeneration.
The key roles of toll-like receptors (TLRs) as mediators of the detection and responses of immune cells to invading pathogens are well known. There are at least 13 mammalian TLRs which are integral membrane proteins with a leucine-rich extracellular domain and a cytoplasmic domain similar to that of the interleukin-1 receptor which initiates downstream signaling through kinases to activate transcription factors such as AP-1 and NFkappaB. TLRs are activated in glial cells (microglia, astrocytes and oligodendrocytes) and lymphocytes that infiltrate the nervous system in response to inflammation caused by infectious agents, tissue injury or autoimmune conditions. By inducing the production of pro-inflammatory cytokines and cell adhesion molecules in immune cells, TLRs may indirectly damage neurons in conditions such as ischemic stroke and multiple sclerosis. Recent findings suggest that neurons also express a subset of TLRs and that their activation promotes neuronal degeneration in experimental models of stroke and Alzheimer's disease. TLRs may also play roles in regulating the processes of neurogenesis and neurite outgrowth, suggesting roles in neuronal plasticity. A better understanding of the molecular and cellular biology of TLRs in the normal and diseased nervous system, may lead to novel approaches for preventing neuronal degeneration and promoting recovery of function in an array of neurodegenerative conditions.


Trimetazidine and inflammatory response in coronary artery bypass grafting.
Organic inflammatory response is a pathophysiological mechanism present at every coronary artery bypass grafting with extracorporeal circulation (CABG-ECC), the release of inflammatory mediators being one of its defense mechanisms. To assess, in a prospective double-blind randomized and placebo-controlled study, the effects of trimetazidine (Tmz) on the inflammatory response, by using the variation in interleukins 6 and 8, TNF-α, complements C3 and C5, and highly sensitive C-reactive protein (HS-CRP) levels in the pre- and post-operative periods. This study assessed 30 patients undergoing CABG-ECC with intermittent hypothermic cardioplegia, and having, at most, mild ventricular dysfunction. The patients were divided into two groups (placebo and Tmz), stratified by echocardiography, and received drug/placebo at the dose of 60 mg/day. Measurements were taken as follows: in the pre-operative period with no drug; on the day of surgery, corresponding to 12 to 15 days on drug/placebo; five minutes after aortic unclamping; 12 and 24 hours after surgery, for interleukins and complements; and 48 hours after surgery, for HS-CRP. No significant difference between the levels of interleukin 8, TNF-α, C3 and C5, and HS-CRP was observed. However, the interleukin 6 levels were significantly lower in the group treated as compared with those in the control group at all time points assessed. Trimetazidine proved to be effective only for reducing interleukin 6 in patients undergoing CABG.


Management of injuries to the porta hepatis.
The management of injuries to the porta hepatis is challenging and controversial. Although definitive, anatomic reconstruction of injured ductal or vascular structures is optimal, porta hepatis injuries are universally accompanied by injuries to other organs (3.6 in this series), which often precludes initial repair. Moreover, frequent injury to the inferior vena cava, aorta, or other major blood vessels in addition to the structures of the porta hepatis results in these injuries being treated in conjunction with exsanguinating hemorrhage. For that reason, control of hemorrhage is the initial management priority, with the initial operation requiring expeditious, if less than anatomically exact, operations. Eighteen of 31 patients survived porta hepatis injury. Hepatic artery injuries were treated by ligation. Complex injuries to bile ducts frequently required enteric-ductal anastomoses as secondary procedures. Of 29 patients with portal vein injuries, six were treated by ligation, 22 by lateral repair, and one with splenic vein interposition graft. As in earlier reports, the structure of the porta hepatis associated with the highest morbidity and mortality rates when injured was the portal vein.


Mineral anisotropy in mineralized tissues is similar among species and mineral growth occurs independently of collagen orientation in rats: results from acoustic velocity measurements.
It has been reported that the mineral crystals in long bones have their c-axis aligned with the bone axis, presumably because collagen fibrils in bone also align with the bone axis. However, the predominant collagen orientation in bone often does not appear to be aligned with the mineral crystals, especially in rat primary bone. We hypothesized that mineral orientation in bone is not necessarily related to collagen orientation. An acoustic microscope was used to measure elastic constants of mineralized tissues from rat, cow, monkey, and human bone, and mineralized turkey leg tendon (MTLT). Measurements were made before and after demineralization with 10% ethylenediaminetetraacetic acid (EDTA) or decollagenization with 7% sodium hypochlorite. The elastic anisotropy ratio (AR) was defined as the ratio of the elastic coefficient in the longitudinal direction to the elastic coefficient in the transverse direction. Anisotropy ratios of mineralized tissues were not affected by formalin fixation or plastic embedding. An evaluation of tissues from the different species showed that the AR after decollagenization was not significantly different (p > 0.4, analysis of variance) among the groups, while AR after demineralization varied from 1.04 (rat bone) to 1.51 (MTLT). There was no correlation between AR after demineralization and AR after decollagenization (r = 0.13, p = 0.5). This showed that the elastic anisotropy of collagen is more variable than mineral anisotropy in bone and MTLT. Another experiment showed that mineralization of turkey leg tendon changes the elasticity of the collagen matrix, making it less anisotropic. A final, prospective experiment was performed in which tibiae of rats were subjected to mechanical loading for 16 weeks. After 12 days, new periosteal woven bone was observed on the tibiae and, after 16 weeks, this new bone was consolidated and mineralized. Mineral in the newly formed woven bone was virtually isotropic (AR = 1.07) after 12 days of loading, then became more anisotropic (AR = 1.52) after 16 weeks of mechanical loading, as the mineral density of the new bone increased. This increase in anisotropy of bone mineral occurred even though the collagen matrix was woven and had no measureable fibril orientation. We conclude that (1) collagen anisotropy and mineral anisotropy are not necessarily correlated in mineralized tissues, (2) mineralization can affect the collagen matrix elasticity of mineralized tissues, and (3) an organized mineral structure can form in the absence of an organized collagen matrix.


Physical activity (PA) and sleep among children and adolescents with cancer.
Although sleep and physical activity often are impaired among adult cancer patients, there is limited data among pediatric oncology populations. We conducted a prospective study to investigate the relationship between physical activity (PA) and sleep among children with cancer. Between 11/12/09 and 02/06/12, PA while awake and sleep variables were assessed by actigraphy collected over 7 days in 36 children (age range 8-18 years) with cancer (23 leukemia/lymphoma, 5 brain tumor, 8 solid tumor). Sleep diaries were used to determine sleep time, sleep quality, and morning mood. Fatigue was assessed at study initiation using fatigue instruments. Participants had impaired sleep based upon normative data compiled from multiple studies of more than 1,700 healthy children from 1 to 18 years of age [1], including decreased total sleep time (mean 6.6 hours, standard deviation (SD) 1.3 hours), increased wake after sleep onset (WASO; mean 2 hours, SD 1.4 hours), increased awakenings during sleep (mean 28.3 wake bouts, SD 7.8 bouts), and decreased sleep efficiency (mean 74.2%, SD 13.3%). Fatigue correlated with self-reported sleep quality but not with disturbances in sleep as measured by actigraphy. In longitudinal models that controlled for age, diagnosis group, gender, race, and steroid use, higher average activity, as measured by actigraphy, was associated with improved sleep quantity (P = 0.005) and efficiency (P = 0.001). Pediatric oncology patients demonstrate impaired sleep. Greater PA was significantly associated with improved sleep quantity and efficiency in pediatric oncology participants. As a potentially modifiable factor, PA may offer a mechanism to improve sleep in pediatric oncology patients.


Association of zoonotic Ljungan virus with intrauterine fetal deaths.
It has recently been shown that Ljungan virus (LV) is associated with disease in its wild rodent reservoir. In addition, it has been demonstrated that LV causes malformations and perinatal death in a mouse model. The question was therefore raised whether LV is a zoonotic agent in humans. Population fluctuations of native rodents in Sweden were compared to the incidence of intrauterine fetal deaths (IUFDs) using the Swedish national hospitalization database. Formalin-fixed tissues from cases of IUFD were investigated using LV-specific immunohistochemistry. Variation in the incidence of IUFDs closely tracked the fluctuations in native rodent populations. LV was detected in the brain tissue in 4 of 10 cases of IUFDs investigated by immunochemistry. LV was also detected in the placenta in 5 of the 10 IUFD cases, but in none of 20 placentas from normal pregnancies. LV may play an important role in IUFDs.


Public preferences for colorectal cancer screening tests: a review of conjoint analysis studies.
A wide range of screening technologies is available for colorectal cancer screening. There is demand to discover public preferences for these tests on the rationale that tailoring screening to preferences may improve uptake. This review describes a type of study (conjoint analysis) used to assess people's preferences for colorectal cancer screening tests and critically evaluates research quality using a recently published set of guidelines. Most primary studies assessed preferences for colonoscopy and fecal occult blood testing but newer technologies (e.g., capsule endoscopy) have not yet been evaluated. Although studies often adhered to guidelines, there was limited correspondence between stated preferences and actual screening behavior. Future research should investigate how studies can go beyond the guidelines in order to improve this and also explore how test preferences may differ by important population subgroups.


Population attributable risks of modifiable reproductive factors for breast and ovarian cancers in Korea.
Breast and ovarian cancers are predominant female cancers with increasing prevalence. The purpose of this study was to estimate the population attributable risks (PARs) of breast and ovarian cancer occurrence based on the relative risks (RRs) of modifiable reproductive factors and population-specific exposure prevalence. The PAR was calculated by using the 1990 standardized prevalence rates, the 2010 national cancer incidence with a 20 year lag period, the meta-analyzed RRs from studies conducted in the Korean population for breast cancer, and the meta-analyzed RRs from a Korean epithelial ovarian cancer study and a prior meta-analysis, and ovarian cancer cohort results up to 2012. For oral contraceptive and hormone replacement therapy use, we did not consider lag period. The summary PARs for modifiable reproductive factors were 16.7% (95% CI 15.8-17.6) for breast cancer (2404 cases) and 81.9% (95% CI 55.0-100.0) for ovarian cancer (1579 cases). The modifiable reproductive factors included pregnancy/age at first birth (8.0%), total period of breastfeeding (3.1%), oral contraceptive use (5.3%), and hormone replacement therapy use (0.3%) for breast cancer and included breastfeeding experience (2.9%), pregnancy (1.2%), tubal ligation (24.5%), and oral contraceptive use (53.3%) for ovarian cancer. Despite inherent uncertainties in the risk factors for breast and ovarian cancers, we suggest that appropriate long-term control of modifiable reproductive factors could reduce breast and ovarian cancer incidences and their related burdens by 16.7% and 81.9%, respectively.


A special pattern of the smooth endoplasmic reticulum in the kidney of the snail Cryptomphalus aspersa.
A special structural pattern of the smooth endoplasmic reticulum (SER) has been observed in the kidney of the snail Cryptomphalus aspersa. Two types of cells (clear and dark) cover the foldings of the renal sac; the dark cells are by far the most numerous. A cisterna of SER enveloping the nucleus appears invariably in both types of cells, with no disruptions, or small ones (from 50 to 90 nm) along its profile. The layer of cytoplasm lodged between the external nuclear membrane and this cisterna is found invariably to be from 0-20 to 0-25 mum in width. Glycogen is abundant in the cytoplasm as alpha particles, and also in the nucleus, but as beta particles. It is noteworthy that absolutely no glycogen is present in the layer of cytoplasm lodged between the nuclear membrane and the surrounding SER envelope. Long profiles of SER are also observed closely approaching and parallel to the plasma membrane of the dark cells. Considering the role of SER in glycogen metabolism in the kidney of the snail, the possible function of these cisternae as a support system ofr enzymes involved in the metabolism of glucides is discussed.


Rocky Mountain Spotted Fever and Pregnancy: Four Cases from Sonora, Mexico.
We present a series of four pregnant women with Rocky Mountain spotted fever (RMSF) that occurred in Sonora, Mexico, during 2015-2016. Confirmatory diagnoses were made by polymerase chain reaction or serological reactivity to antigens of Rickettsia rickettsii by using an indirect immunofluorescence antibody assay. Each patient presented with fever and petechial rash and was treated successfully with doxycycline. Each of the women and one full-term infant delivered at 36 weeks gestation survived the infection. Three of the patients in their first trimester of pregnancy suffered spontaneous abortions. RMSF should be suspected in any pregnant woman presenting with fever, malaise and rash in regions where R. rickettsii is endemic.


Expression and validation of D-erythrulose 1-phosphate dehydrogenase from Brucella abortus: a diagnostic reagent for bovine brucellosis.
Brucella abortus is a bacterium of brucellosis causing abortion in cattle. The diagnosis of bovine brucellosis mainly relies on serologic tests using smooth lipopolysaccharide (S-LPS) from B. abortus. However, the usefulness of this method is limited by false-positive reactions due to cross-reaction with other Gram-negative bacteria. In the present study, the eryC gene encoding B. abortus d-erythrulose 1-phosphate dehydrogenase, which is involved in the erythritol metabolism in virulent B. abortus strain but is absent from a B. abortus vaccine strain (S19), was cloned. Recombinant EryC was expressed and purified for the evaluation as a diagnostic reagent for bovine brucellosis. Other B. abortus proteins, Omp16, PP26, and CP39 were also purified and their seroreactivities were compared. Recombinant EryC, Omp16, PP26, and PP39 were all reactive to B. abortus-positive serum. The specificity of recombinant Omp16, PP26, CP39, and EryC, were shown to be approximately 98%, whereas that of B. abortus whole cell lysates was shown to be 95%. The sensitivity of Omp16, PP26, CP39, and EryC were 10%, 51%, 64%, and 43%, respectively, whereas that of B. abortus whole cell lysates was 53%. These results suggested that B. abortus EryC would be a potential reagent for diagnosis for bovine brucellosis as a single protein antigen.


Omeprazole: a new drug for the treatment of acid-peptic diseases.
Omeprazole is the first of a new class of gastric antisecretory drugs, proton pump inhibitors. It inhibits the H+,K(+)-adenosinetriphosphatase enzyme of the gastric parietal cell, resulting in potent, long-lasting suppression of basal and stimulated acid secretion. The drug is currently approved for treatment of gastroesophageal reflux disease and Zollinger-Ellison syndrome. In clinical trials, treatment with omeprazole results in rapid healing of duodenal ulcers; it is also effective in treating gastric ulcer disease. It is uniformly well tolerated without significant adverse effects, although animal studies linked profound long-term suppression of gastric acid secretion with the development of gastric carcinoids. Potential future uses include the prophylaxis of ulceration secondary to stress or use of nonsteroidal anti-inflammatory drugs, and the prophylaxis of recurrent peptic ulcer disease.


A cohort study of factors influencing the physical fitness of preschool children: a decision tree analysis.
Based on the decision tree model, to explore the key influencing factors of children's physical fitness, rank the key influencing factors, and explain the complex interaction between the influencing factors. A cohort study design was adopted. 1,276 children (ages 3-6) from 23 kindergartens in Nanchang, China, were chosen for the study to measure the children's physical fitness at baseline and a year later and to compare the physical fitness scores at the two stages. The study was conducted following the Chinese National Physical Fitness Testing Standard (Children Part); To identify the primary influencing factors of changes in physical fitness, a decision tree model was developed, and a questionnaire survey on birth information, feeding patterns, SB, PA, dietary nutrition, sleep, parental factors, and other relevant information was conducted. The levels of physical fitness indicators among preschool children showed a significant increase after 1 year. The accuracy of the CHAID model is 84.17%. It showed that 7 variables were strongly correlated with the physical changes of children's fitness, the order of importance of each variable was weekend PA, weekend MVPA, mother's BMI, mother's sports frequency, father's education, mother's education, and school day PA. Three factors are related to PA. Four factors are related to parental circumstances. In addition to the seven important variables mentioned, variables such as breakfast frequency on school day, puffed food, frequency of outing, school day MVPA, parental feeling of sports, father's occupation, and weekend breakfast frequency are all statistically significant leaf node variables. PA, especially weekend PA, is the most critical factor in children's physical fitness improvement and the weekend MVPA should be increased to more than 30 min/d based on the improvement of weekend PA. In addition, parental factors and school day PA are also important in making decisions about changes in fitness for children. The mother's efforts to maintain a healthy BMI and engage in regular physical activity are crucial for enhancing the physical fitness of children. Additionally, other parental factors, such as the parents' educational levels and the father's occupation, can indirectly impact the level of physical fitness in children.


COALA: A Protocol for the Avoidance and Alleviation of Congestion in Wireless Sensor Networks.
The occurrence of congestion has an extremely deleterious impact on the performance of Wireless Sensor Networks (WSNs). This article presents a novel protocol, named COALA (COngestion ALleviation and Avoidance), which aims to act both proactively, in order to avoid the creation of congestion in WSNs, and reactively, so as to mitigate the diffusion of upcoming congestion through alternative path routing. Its operation is based on the utilization of an accumulative cost function, which considers both static and dynamic metrics in order to send data through the paths that are less probable to be congested. COALA is validated through simulation tests, which exhibit its ability to achieve remarkable reduction of loss ratios, transmission delays and energy dissipation. Moreover, the appropriate adjustment of the weighting of the accumulative cost function enables the algorithm to adapt to the performance criteria of individual case scenarios.


Exploring social media and admissions decision-making - friends or foes?
Despite the ever-increasing use of social media (e.g., Facebook, Twitter) little is known about its use in medical school admissions. This qualitative study explores whether and how social media (SM) is used in undergraduate admissions in Canada, and the attitudes of admissions personnel towards such use. Phone interviews were conducted with admissions deans and nominated admissions personnel. A qualitative descriptive analysis was performed using iterative coding and comparing, and grouping data into themes. Personnel from 15 of 17 Canadian medical schools participated. A sizeable proportion had, at some point, examined social media (SM) profiles to acquire information on applicants. Participants did not report using it explicitly to screen all applicants (primary use); however, several did admit to looking at SM to follow up on preliminary indications of misbehaviour (secondary use). Participants articulated concerns, such as validity and equity, about using SM in admissions. Despite no schools having existing policy, participants expressed openness to future use. While some of the 15 schools had used SM to acquire information on applicants, criteria for formulating judgments were obscure, and participants expressed significant apprehension, based on concerns for fairness and validity. Findings suggest participant ambivalence and ongoing risks associated with "hidden" selection practices.


Patterns of molecular evolution associated with two selective sweeps in the Tb1-Dwarf8 region in maize.
We focused on a region encompassing a major maize domestication locus, Tb1, and a locus involved in the flowering time variation, Dwarf8 (D8), to investigate the consequences of two closely linked selective sweeps on nucleotide variation and gain some insights into maize geographical diffusion, through climate adaptation. First, we physically mapped D8 at approximately 300 kb 3' of Tb1. Second, we analyzed patterns of nucleotide variation at Tb1, D8, and seven short regions (400-700 bp) located in the Tb1-D8 region sequenced on a 40 maize inbred lines panel encompassing early-flowering temperate and late-flowering tropical lines. The pattern of polymorphism along the region is characterized by two valleys of depleted polymorphism while the region in between exhibits an appreciable amount of diversity. Our results reveal that a region approximately 100 kb upstream of the D8 gene exhibits hallmarks of divergent selection between temperate and tropical lines and is likely closer than the D8 gene to the target of selection for climate adaptation. Selection in the tropical lines appears more recent than in the temperate lines, suggesting an initial domestication of early-flowering maize. Simulation results indicate that the polymorphism pattern is consistent with two interfering selective sweeps at Tb1 and D8.


Antibody Responses Against Anopheles darlingi Immunogenic Peptides in Plasmodium Infected Humans.
Introduction: Malaria is still an important vector-borne disease in the New World tropics. Despite the recent decline in malaria due to Plasmodium falciparum infection in Africa, a rise in Plasmodium infections has been detected in several low malaria transmission areas in Latin America. One of the main obstacles in the battle against malaria is the lack of innovative tools to assess malaria transmission risk, and the behavioral plasticity of one of the main malaria vectors in Latin America, Anopheles darlingi. Methods: We used human IgG antibodies against mosquito salivary gland proteins as a measure of disease risk. Whole salivary gland antigen (SGA) from Anopheles darlingi mosquitoes was used as antigen in Western blot experiments, in which a ~65 kDa protein was visualized as the main immunogenic band and sent for sequencing by mass spectrometry. Apyrase and peroxidase peptides were designed and used as antigens in an ELISA-based test to measure human IgG antibody responses in people with different clinical presentations of malaria. Results: Liquid chromatography-mass spectrometry revealed 17 proteins contained in the ~65 kDa band, with an apyrase and a peroxidase as the two most abundant proteins. Detection of IgG antibodies against salivary antigens by ELISA revealed a significant higher antibody levels in people with malaria infection when compared to uninfected volunteers using the AnDar_Apy1 and AnDar_Apy2 peptides. We also detected a significant positive correlation between the anti-peptides IgG levels and antibodies against the Plasmodium vivax and P. falciparum antigens PvMSP1 and PfMSP1. Odd ratios suggest that people with higher IgG antibodies against the apyrase peptides were up to five times more likely to have a malaria infection. Conclusion: Antibodies against salivary peptides from An. darlingi salivary gland proteins may be used as biomarkers for malaria risk.


Functional annotation of risk loci identified through genome-wide association studies for prostate cancer.
The majority of established prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) identified from genome-wide association studies do not fall into protein coding regions. Therefore, the mechanisms by which these SNPs affect PCa risk remain unclear. Here, we used a series of bioinformatic tools and databases to provide possible molecular insights into the actions of risk SNPs. We performed a comprehensive assessment of the potential functional impact of 33 SNPs that were identified and confirmed as associated with PCa risk in previous studies. For these 33 SNPs and additional SNPs in linkage disequilibrium (LD) (r(2) ≥ 0.5), we first mapped them to genomic functional annotation databases, including the encyclopedia of DNA elements (ENCODE), 11 genomic regulatory elements databases defined by the University of California Santa Cruz (UCSC) table browser, and androgen receptor (AR)-binding sites defined by a ChIP-chip technique. Enrichment analysis was then carried out to assess whether the risk SNP blocks were enriched in the various annotation sets. Risk SNP blocks were significantly enriched over that expected by chance in two annotation sets, including AR-binding sites (P = 0.003), and FoxA1-binding sites (P = 0.05). About one-third of the 33 risk SNP blocks are located within AR-binding regions. The significant enrichment of risk SNPs in AR-binding sites may suggest a potential molecular mechanism for these SNPs in PCa initiation, and provide guidance for future functional studies.


Interaction of paraquat and amine uptake by rat lungs perfused in situ.
The kinetics of [14C]paraquat (N,N-di[14C]methyl-4,4'-bipyridylium) uptake from the pulmonary circulation were investigated in rat lungs perfused in situ. During the 1st h of exposure to the herbicide paraquat entered the lungs primarily by diffusion; no evidence was obtained from concentrative uptake, saturation kinetics (1-3,500 microM paraquat), or inhibition by the amines methyl-glyoxal bis(guanylhydrazone) or spermidine, both of which were expected to compete for paraquat transport sites. In contrast, after 60 min of exposure, uptake rates increased two- to three-fold, and paraquat was accumulated to an apparent intracellular concentration greater than that in the perfusate. The latter phase of paraquat uptake was saturable and was inhibited by methylglyoxal bis(guanylhydrazone); it did not appear to reflect a progressive paraquat-induced alteration in cellular permeability but rather predominance of a rapid, carrier-mediated uptake pathway.


Clinical and dermoscopic characteristics of amelanotic melanomas that are not of the nodular subtype.
Amelanotic melanomas remain challenging to diagnose. To analyze and describe the clinical and dermoscopic characteristics of amelanotic melanomas that are not of the nodular subtype. We conducted a retrospective review of 20 consecutively diagnosed amelanotic melanomas. The clinical and dermoscopic images of pathologically confirmed amelanotic melanomas that were not of the nodular subtype were analyzed. In addition, the clinical diagnosis and the reasons why these lesions were biopsied were examined. All 20 amelanotic melanomas were erythematous and lacked any of the clinical ABCD features commonly attributed to melanoma. The lesions appeared clinically to be relatively symmetric with regular borders and manifesting a circular to oval morphology. Dermoscopically, all lesions manifested polymorphous vascular pattern. Amelanotic melanomas that are not of the nodular subtype often present as clinically symmetric erythematous lesions. Therefore, it is important to consider AMs in the differential diagnosis of isolated and persistent erythematous outlier lesions, even if they are symmetric in appearance. Additionally, the presence of a polymorphous vascular pattern seen with dermoscopy can facilitate in correctly identifying these melanomas.


Addition of anti-estrogen therapy to anti-HER2 dendritic cell vaccination improves regional nodal immune response and pathologic complete response rate in patients with ERpos/HER2pos early breast cancer.
HER2-directed therapies are less effective in patients with ERpos compared to ERneg breast cancer, possibly reflecting bidirectional activation between HER2 and estrogen signaling pathways. We investigated dual blockade using anti-HER2 vaccination and anti-estrogen therapy in HER2pos/ERpos early breast cancer patients. In pre-clinical studies of HER2pos breast cancer cell lines, ERpos cells were partially resistant to CD4+ Th1 cytokine-induced metabolic suppression compared with ERneg cells. The addition of anti-estrogen treatment significantly enhanced cytokine sensitivity in ERpos, but not ERneg, cell lines. In two pooled phase-I clinical trials, patients with HER2pos early breast cancer were treated with neoadjuvant anti-HER2 dendritic cell vaccination; HER2pos/ERpos patients were treated with or without concurrent anti-estrogen therapy. The anti-HER2 Th1 immune response measured in the peripheral blood significantly increased following vaccination, but was similar across the three treatment groups (ERneg vaccination alone, ERpos vaccination alone, ERpos vaccination + anti-estrogen therapy). In the sentinel lymph nodes, however, the anti-HER2 Th1 immune response was significantly higher in ERpos patients treated with combination anti-HER2 vaccination plus anti-estrogen therapy compared to those treated with anti-HER2 vaccination alone. Similar rates of pathologic complete response (pCR) were observed in vaccinated ERneg patients and vaccinated ERpos patients treated with concurrent anti-estrogen therapy (31.4% vs. 28.6%); both were significantly higher than the pCR rate in vaccinated ERpos patients who did not receive anti-estrogen therapy (4.0%, p = 0.03). Since pCR portends long-term favorable outcomes, these results support additional clinical investigations using HER2-directed vaccines in combination with anti-estrogen treatments for ERpos/HER2pos DCIS and invasive breast cancer.


Cytoskeleton stability is essential for the integrity of the cerebellum and its motor- and affective-related behaviors.
The cerebellum plays a key role in motor tasks, but its involvement in cognition is still being considered. Although there is an association of different psychiatric and cognitive disorders with cerebellar impairments, the lack of time-course studies has hindered the understanding of the involvement of cerebellum in cognitive and non-motor functions. Such association was here studied using the Purkinje Cell Degeneration mutant mouse, a model of selective and progressive cerebellar degeneration that lacks the cytosolic carboxypeptidase 1 (CCP1). The effects of the absence of this enzyme on the cerebellum of mutant mice were analyzed both in vitro and in vivo. These analyses were carried out longitudinally (throughout both the pre-neurodegenerative and neurodegenerative stages) and different motor and non-motor tests were performed. We demonstrate that the lack of CCP1 affects microtubule dynamics and flexibility, defects that contribute to the morphological alterations of the Purkinje cells (PCs), and to progressive cerebellar breakdown. Moreover, this degeneration led not only to motor defects but also to gradual cognitive impairments, directly related to the progression of cellular damage. Our findings confirm the cerebellar implication in non-motor tasks, where the formation of the healthy, typical PCs structure is necessary for normal cognitive and affective behavior.


Cutaneous manifestations of blastic plasmacytoid dendritic cell neoplasm-morphologic and phenotypic variability in a series of 33 patients.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a neoplasm derived from precursors of plasmacytoid dendritic cells. Cutaneous involvement represents often the first manifestation of the disease. We studied 45 skin biopsies from 33 patients (M:F=7.25:1; median age: 71 y; age range: 30 to 89) with BPDCN to delineate histopathologic and immunophenotypic features of this disease. Patients presented with generalized (n=18), localized (n=6), or solitary (n=9) macules, plaques, and/or tumors. Staging investigations at presentation were negative in 20 patients. Unusual histologic features included a perivascular/periadnexal pattern (6 biopsies from 4 patients) and the presence of pleomorphism of neoplastic cells with blastoid cells admixed with elongated, twisted, or hyperchromatic cells (observed in 24 specimens). Negativity of 1 among the 4 markers CD4, CD56, CD123, and TCL-1 was seen in 11 biopsies, and of 2 markers in 4 biopsies. Staining for CD68 revealed positivity of the majority of cells in 1 and of scattered cells in 24/37 stained cases. Terminal deoxynucleotidyl transferase was observed in 22/37 stained cases. Staining for Bcl-6, MUM-1 and FOX-P1 revealed positivity of a variable proportion of neoplastic cells in 16/30, 19/29, and 21/23 cases, respectively. Our study shows that cutaneous lesions of BPDCN display a greater variability of morphologic and phenotypic features than recognized earlier. Discrete perivascular infiltrates, pleomorphic morphology of neoplastic cells, and unusual phenotypic profiles may be the source of diagnostic pitfalls. These atypical variants should be recognized to make an early diagnosis and to manage properly patients with this aggressive hematological disorder.


A stereological analysis of venous nicking observed at retinal arteriovenous crossings.
The accepted hypotheses for the explanation of retinal venous nicking are critically reviewed and an alternative hypothesis based on a stereological analysis is presented. The ophthalmoscopic appearance of retinal venous nicking is best explained by partial collapse of the vein with the major axis of the venous cross section at right angles to the internal limiting a membrane of the venous blood flow nor of the likelihood of tributary vein occlusion. A partially collapsed vein may be very sensitive to small changes in intraocular pressure. Patients with impending tributary vein occlusion may benefit from reducing intraocular pressure.


Controlling a robot with intention derived from motion.
We present a novel, sophisticated intention-based control system for a mobile robot built from an extremely inexpensive webcam and radio-controlled toy vehicle. The system visually observes humans participating in various playground games and infers their goals and intentions through analyzing their spatiotemporal activity in relation to itself and each other, and then builds a coherent narrative out of the succession of these intentional states. Starting from zero information about the room, the rules of the games, or even which vehicle it controls, it learns rich relationships between players, their goals and intentions, probing uncertain situations with its own behavior. The robot is able to watch people playing various playground games, learn the roles and rules that apply to specific games, and participate in the play. The narratives it constructs capture essential information about the observed social roles and types of activity. After watching play for a short while, the system is able to participate appropriately in the games. We demonstrate how the system acts appropriately in scenarios such as chasing, follow-the-leader, and variants of tag.


Downstream targets of the Phytophthora infestans Galpha subunit PiGPA1 revealed by cDNA-AFLP.
SUMMARY In many plant pathogens heterotrimeric G-proteins are essential signalling components involved in development and pathogenicity. In the late blight oomycete pathogen Phytophthora infestans the G-protein alpha subunit PiGPA1 controls zoospore motility and is required for virulence. To identify G-protein targets and signalling pathways downstream of PiGPA1, we used an optimized cDNA-AFLP protocol for analysing gene expression profiles in hypovirulent P. infestans strains that were previously generated by silencing the Pigpa1 gene. First, expression profiles in sporangia and mycelium of the wild-type strain were compared, and this revealed a substantial number of mycelium- or sporangia-specific transcript derived fragments (TDFs). Subsequently, profiles in sporangia of wild-type, Pigpa1-silenced mutants and of a strain expressing a constitutively active form of PiGPA1 were compared. From a total of 2860 TDFs, 92 were down- and 19 up-regulated in the Pigpa1-silenced mutants. A subset of the differential TDFs was cloned and sequenced, and homology searches were carried out against Phytophthora EST and genomic databases and the NCBI database. cDNA-AFLP expression profiles were verified by Northern blot analysis or RT-PCR. The power of cDNA-AFLP for the identification of target genes in knock-down or gain-of-function mutants is discussed.


Challenges to sourcing human bodies for teaching and research in Africa: Are the challenges insurmountable?
The teaching and learning of human anatomy by dissection has existed for thousands of years. Over the centuries, evolving ethical considerations for the sourcing of human bodies for dissection have resulted in a transition from the use of unconsented individuals to that of body donors and the institution of body donation programmes around the world. However, major challenges on the Africa continent have resulted in the continued use of unconsented or unclaimed bodies and the ethical dilemma for African anatomy departments regarding their use. Some of the key difficulties in sourcing donor bodies which exist on the African continent emanate from religious, cultural, societal trust and other confounding factors. This manuscript explores the challenges and suggest ways in which some of these constraints may be overcome.


Serotonergic 5-HT6 Receptor Antagonists: Heterocyclic Chemistry and Potential Therapeutic Significance.
The serotonin 5-HT(6) receptor (5- HT(6)R) is amongst the recently discovered serotonergic receptors with almost exclusive localization in the brain. Hence, this receptor is fast emerging as a promising target for cognition enhancement in central nervous system (CNS) diseases such as Alzheimer's disease (cognitive function), obesity, schizophrenia and anxiety. The last decade has seen a surge of literature reports on the functional role of this receptor in learning and memory processes and investigations related to the chemistry and pharmacology of 5-HT(6) receptor ligands, especially 5- HT(6) receptor antagonists. Studies show the involvement of multiple neurotransmitter systems in cognitive enhancement by 5-HT(6)R antagonists including cholinergic, glutamatergic, and GABAergic systems. Several of the 5-HT(6)R ligands are indole based agents bearing structural similarity to the endogenous neurotransmitter serotonin. Based on the pharmacophoric models proposed for these agents, drug designing has been carried out incorporating various heterocyclic replacements for the indole nucleus. In this review, we have broadly summarized the medicinal chemistry and current status of this fairly recent class of drugs along with their potential therapeutic applications.


Patients' perceived purpose of clinical informed consent: Mill's individual autonomy model is preferred.
Although informed consent is an integral part of clinical practice, its current doctrine remains mostly a matter of law and mainstream ethics rather than empirical research. There are scarce empirical data on patients' perceived purpose of informed consent, which may include administrative routine/courtesy gesture, simple honest permission, informed permission, patient-clinician shared decision-making, and enabling patient's self decision-making. Different purposes require different processes. We surveyed 488 adults who were planning to undergo or had recently undergone written informed consent-requiring procedures. Perceptions of informed consent purpose (from norm and current practice perspectives) were explored by asking respondents to rank (1 = most reflective) 10 randomly-presented statements: "meaningless routine", "courtesy gesture" "litigation protection", "take away compensation rights", "inform patient', "make sure patient understand", "document patient's decision", "discover patient's preferences", "have shared decision", and "help patient decide". Respondents' mean (SD) age was 38.3 (12.5); 50.4% were males, 56.8% had ≥ college education, and 37.3% had undergone a procedure. From the norm perspective, the least reflective statement was "meaningless routine" (ranked 1-3 by 2.6% of respondents) and the most reflective statements were "help patient decide", "make sure patient understand", and "inform patient" (ranked 1-3 by 65%, 60%, and 48% of respondents with median [25%,75%] ranking scores of 2 [1,5], 3 [2,4], and 4 [2,5], respectively). Compared to their counterparts, males and pre-procedure respondents ranked "help patient decide" better, whereas females and post-procedure respondents ranked "inform patient" better (p = 0.007 to p < 0.001). Age was associated with better ranking of "help patient decide" and "make sure patient understand" statements (p < 0.001 and p = 0.002, respectively), which were ranked 1-3 by only 46% and 42% of respondents from the current practice perspective (median ranking score 4 [2,6], p < 0.001 vs. norm perspective for both). 1) the informed consent process is important to patients, however, patients vary in their views of its purpose with the dominant view being enabling patients' self decision-making, 2) males, pre-procedure, and older patients more favor a self decision-making purpose, whereas females and post-procedure patients more favor an information disclosure purpose, and 3) more self decision-making and more effective information disclosure than is currently practiced are desired. An informed consent process consistent with Mill's individual autonomy model may be suitable for most patients.


Suppression of Transposable Elements in Leukemic Stem Cells.
Genomic transposable elements (TEs) comprise nearly half of the human genome. The expression of TEs is considered potentially hazardous, as it can lead to insertional mutagenesis and genomic instability. However, recent studies have revealed that TEs are involved in immune-mediated cell clearance. Hypomethylating agents can increase the expression of TEs in cancer cells, inducing 'viral mimicry', causing interferon signalling and cancer cell killing. To investigate the role of TEs in the pathogenesis of acute myeloid leukaemia (AML), we studied TE expression in several cell fractions of AML while tracking its development (pre-leukemic haematopoietic stem cells, leukemic stem cells [LSCs], and leukemic blasts). LSCs, which are resistant to chemotherapy and serve as reservoirs for relapse, showed significant suppression of TEs and interferon pathways. Similarly, high-risk cases of myelodysplastic syndrome (MDS) showed far greater suppression of TEs than low-risk cases. We propose TE suppression as a mechanism for immune escape in AML and MDS. Repression of TEs co-occurred with the upregulation of several genes known to modulate TE expression, such as RNA helicases and autophagy genes. Thus, we have identified potential pathways that can be targeted to activate cancer immunogenicity via TEs in AML and MDS.


Estrous cycle and ovarian changes in a rat mammary carcinogenesis model after irradiation, tamoxifen chemoprevention, and aging.
Variation in the effects of selective estrogen receptor modulators (SERMs) on the estrous cycle and reproductive organs during aging could play an important role in the observed heterogeneity of tamoxifen chemoprevention efficacy against breast cancer. Of the 1,022 female Sprague Dawley rats enrolled in a long-term tamoxifen chemoprevention study, 87 were randomly chosen from four groups (irradiated, irradiated and tamoxifen treated, tamoxifen treated, and control). Vaginal smears were evaluated for determination of cycle stage, and vaginal pathologic changes. Correlation with the histologic features of reproductive tissues in 43 animals was made. More tamoxifen-treated (21.9%; 7/32) rats had irregular cycling than did control (9%; 3/23) rats. Ovarian granulosa cell hyperplasia was present in 50% (3/6) of tamoxifen-treated rats, and 20% (2/10) of control rats. Endometrial-type cells (ETCs) were present only in tamoxifen-treated (tamoxifen alone 6.25% [2/32]) and tamoxifen/ radiation-treated (28.6% [4/14]) rats. The modified Papanicolaou stain used here provided excellent morphologic detail for evaluating the estrous cycle in rodents. Tamoxifen altered vaginal cytologic and ovarian histologic features during aging. Results indicated that tamoxifen had direct and indirect effects on the reproductive tract, causing disturbance of the estrous cycle, shedding of ETCs, and promoting granulosa cell hyperplasia. Understanding of the heterogeneous response to tamoxifen chemoprevention during aging in rodents may provide important insights into the basis for tamoxifen chemoprevention failures in humans.


Hepatic and gastric amebiasis in black and white colobus monkeys.
Three cases of hepatic amebiasis and one case of gastric amebiasis were diagnosed in black and white colobus monkeys during a 9-month period. The diagnosis was difficult because of the absence of trophozoites and cysts in the feces and because of few trophozoites found in many of the hepatic lesions. Indirect hemagglutination titers were diagnostic in 2 monkeys.


Immune enhancement of yellow fever virus neurovirulence for mice: studies of mechanisms involved.
Enhancement of yellow fever virus neurovirulence for mice by specific antibody was studied with the French neurotropic vaccine strain. Experimental conditions for enhancement required mice between 14 and 40 days old and intraperitoneal administration of a selected monoclonal antibody 24 h before or up to 72 h after intracerebral virus challenge. Virus infectivity titrations were similar in brains of antibody-treated and untreated mice. Virus recovered from brains of mice with enhanced viral infections was neither qualitatively nor quantitatively different from standard virus. Humoral immune responses in enhanced infections were normal, macrophages did not become infected and viraemia was not significant. Both hydrocortisone treatment and complement depletion with cobra venom resulted in prolongation of mouse survival times but virulence enhancement persisted. Antithymocyte serum had no effect on enhancement although it reduced the humoral immune response. It is proposed that virulence enhancement is due to the combined effects of virus-specific antibody on infected cells, complement-mediated cytolysis and resultant host anti-cellular activity. There is no analogy between mechanisms effecting increased arbovirus growth in vitro in the presence of specific antibody and increased yellow fever virus neurovirulence in vivo after parenteral administration of antibody.


Survey of symptoms following intake of pyridostigmine during the Persian Gulf war.
Pyridostigmine bromide, a reversible inhibitor of acetylcholinesterase (AChE), is effectively used as a pre-treatment to organophosphate intoxication. Previous studies have shown that an oral dose of 30 mg twice a day produces a sufficient inhibition of the enzyme activity (20-40%) without causing any significant adverse effect. During the Persian Gulf war pyridostigmine was taken for the first time under a chemical warfare threat. We searched for symptoms and complaints that may be related to the medication. Our survey included 213 soldiers who completed a questionnaire regarding possible symptoms and their severity. AChE inhibition level was compared between groups of soldiers with and without complaints. The most frequent symptoms were nonspecific and included dry mouth, general malaise, fatigue and weakness. Typical effects, such as nausea, abdominal pain, frequent urination and rhinorrhea, were infrequent. The severity of the symptoms was generally mild. The symptoms appeared around 1.6 h after taking the medication and recurred after each intake. No correlation was found between levels of cholinesterase and type or severity of complaints. Anxiety, which accompanies wartime, may have contributed to the appearance of significant symptoms. Further investigations concerning the effects of pyridostigmine ingestion under stressful conditions are warranted.


Influence of nicotine, cotinine, anabasine and cigarette smoke extract on human granulosa cell progesterone and estradiol synthesis.
To reveal the well known effect of smoking on the incidence of early abortion, the possible effects of cigarette alkaloids on progesterone and estradiol synthesis were investigated. A suspected cause for early spontaneous abortion is corpus luteum insufficiency. The present experiments evaluate the effects of cigarette smoke alkaloids on progesterone and estradiol biosynthesis. Human granulosa cells were obtained from patients undergoing in vitro fertilization and embryo transfer treatment because of infertility. Incubation of the granulosa cells with cotinine, anabasine, with the combination of nicotine, cotinine and anabasine, or with an aqueous extract of cigarette smoke resulted in inhibition of progesterone synthesis. The alkaloids and smoke extract decreased the DNA content of the culture dish. These latter findings suggested a cytotoxic effect of the alkaloids. Both cotinine and anabasine slightly stimulated the synthesis of normalized estradiol. However, nicotine, combination of all three alkaloids, and cigarette smoke extract had no significant influence on estradiol production. Taken together, these data would suggest that cigarette alkaloids inhibit cellular progesterone synthesis both by inhibiting progesterone synthesis and by causing less specific toxic effects to the cell. In contrast, cigarette smoke alkaloids slightly stimulated or had no effect on estradiol production. These concomitant actions of cigarette alkaloids partly explain the higher incidence of early abortion in pregnant women who smoke.


Population-based sequencing of the V3 region of env for predicting the coreceptor usage of human immunodeficiency virus type 1 quasispecies.
Genotypic population-based methods could be faster and less expensive than phenotypic recombinant assays for determining human immunodeficiency virus type 1 (HIV-1) coreceptor usage in patient samples, but their clinical use requires good genotype-phenotype correlation and concordance with clonal analyses. We have assessed these requirements by clonal analysis of the V1 to V3 env PCR products of 26 patients infected with subtype B HIV-1. We used the resulting set of molecular clones, all sequenced and characterized using a single-cycle recombinant virus phenotypic entry assay, to reevaluate genotype-phenotype correlations. Combining the previously described 11/25 and net charge rules for the V3 genotype improved the prediction of HIV-1 coreceptor usage. We also evaluated the concordance of population-based and clonal analyses for predicting the coreceptor usage of HIV-1 quasispecies. Our population-based recombinant phenotypic assay and direct sequencing of V3 were similarly sensitive for detecting the presence of minor species in the virus population, and both correlated well with clonal analysis. The improved genotype-phenotype correlation obtained by combining two simple genotypic rules and the good concordance with clonal analyses suggest that direct sequencing of V3 is a valuable alternative to population-based recombinant phenotypic assays.


Formation and characterization of Group IV semiconductor nanowires.
To enable the application to next-generation devices of semiconductor nanowires (NWs), it is important to control their formation and tune their functionality by doping and the use of heterojunctions. In this paper, we introduce formation and the characterization methods of nanowires, focusing on our research results. We describe a top-down method of controlling the size and alignment of nanowires that shows advantages over bottom-up growth methods. The latter technique causes damage to the nanowire surfaces, requiring defect removal after the NW formation process. We show various methods of evaluating the bonding state and electrical activity of impurities in NWs. If an impurity is doped in a NW, mobility decreases due to the scattering that it causes. As a strategy for solving this problem, we describe research into core-shell nanowires, in which Si and Ge heterojunctions are formed in the diameter direction inside the NW. This structure can separate the impurity-doped region from the carrier transport region, promising as a channel for the new ultimate high-mobility transistor.


bcl-2 induction of urokinase plasminogen activator receptor expression in human cancer cells through Sp1 activation: involvement of ERK1/ERK2 activity.
We have previously demonstrated that Bcl-2 overexpression in human breast carcinoma and melanoma cells synergizes with hypoxia to increase angiogenesis through up-regulation of vascular endothelial growth factor. In this work we demonstrated, for the first time, that Bcl-2 overexpression in cancer cells exposed to hypoxia modulates urokinase plasminogen activator receptor (uPAR) expression through Sp1 transcription factor and that the extracellular signal-regulated kinase (ERK) pathway plays a role in Sp1 transcriptional activity. In particular, an increase in uPAR protein and mRNA expression was found in melanoma bcl-2 transfectants grown under hypoxia when compared with control cells, and a decrease of uPAR protein expression was induced by treatment of cells with specific bcl-2 antisense oligonucleotides. Up-regulation of uPAR expression was accompanied by increased Sp1 protein expression, stability, serine phosphorylation, and DNA binding activity. Treatment of cells with mitramycin A, an inhibitor of Sp1 activity, confirmed the role of Sp1 transcriptional activity in uPAR induction by Bcl-2. The contribution of the ERK pathway in Sp1-increased transcriptional activity was demonstrated by the use of chemical inhibition. In fact, ERK kinase activation was induced in Bcl-2-overexpressing cells exposed to hypoxia, and the ERK kinase inhibitor UO126 was able to down-regulate Sp1 phosphorylation and DNA binding activity. Using a human breast carcinoma line, we obtained data supporting our findings with melanoma cells and identified a link between the induction of Sp1 and uPAR expression as a common bcl-2-controlled phenomenon in human tumors. In conclusion, our results strongly indicate that up-regulation of uPAR expression by Bcl-2 in hypoxia is modulated by Sp1 DNA binding activity through the ERK signaling pathway.


Lung cancer and use of cigarettes: a French case-control study.
A case-control study of 1,625 cases and 3,091 controls was conducted in France from 1976 to 1980 to compare the effects of different smoking habits, especially the use of filter cigarettes, tobacco types (light or dark), and the use of hand-rolled or manufactured cigarettes on the occurrence of lung cancer. All cases had histologically confirmed lung cancer; the controls were matched by sex, age, hospital of admission, and interviewer. The reported results concern only male nonsmokers and males who smoked (or had smoked) cigarettes exclusively, i.e., a total of 1,217 Kreyberg I and Kreyberg II cancer cases and 1,915 controls. Cigarette smoking was associated with both Kreyberg I and Kreyberg II cell categories although with different relative risks (RR) (17.2 and 3.6, resp.). Within the Kreyberg I category, RR were significantly increased (P less than .0001) with certain indices of duration and intensity of cigarette exposure, such as early age at first cigarette smoked, daily consumption, depth of inhalation, and duration of smoking. A significant difference in risk was found within the Kreyberg I category for nonfilter versus filter cigarette smokers (RR = 18.1 and 10.9, resp.) and dark versus light tobacco smokers (RR = 18.1 and 4.9, resp.) but not for hand-rolled versus manufactured cigarette smokers (RR = 19.8 and 16.0, resp.). When all the covariates were taken into account in a matched logistic regression, lung cancer risks for nonfilter versus filter cigarette smokers was RR = 1.23, for hand-rolled versus manufactured cigarette users RR = 1.22, and for dark versus light tobacco users RR = 1.94.


Central effects of substance P and somatostatin in conscious, streptozotocin-treated rats.
Cardiovascular responses to intracerebroventricular (icv) injections of substance P and somatostatin were measured in Long-Evans and Brattleboro rats treated with streptozotocin (STZ) or saline. Substance P icv evoked similar pressor responses and tachycardia in STZ-treated and saline-treated Long-Evans rats, together with signs of behavioral activation (i.e., arousal). As a group, Brattleboro rats did not respond significantly to icv substance P, although some individual rats showed clear cardiovascular and behavioral responses. These findings may indicate a reduced sensitivity to icv substance P in Brattleboro rats but show no differences attributable to STZ treatment. Hence, diminished pressor responses to icv angiotensin II (observed previously) may be specific to sympathoadrenal activation associated with drinking. Somatostatin caused a pressor effect in saline-treated, but not in STZ-treated, Long-Evans rats, which was probably due to arginine vasopressin (AVP)-mediated mechanisms because it was not present in either saline-treated or STZ-treated Brattleboro rats. Both control and STZ-treated Long-Evans rats showed a bradycardic response to somatostatin that was not seen in Brattleboro rats. These results indicate that different AVP-mediated mechanisms might be responsible for the pressor and bradycardic effects of icv somatostatin. It is possible that impairment of central somatostatin-mediated AVP release contributes to the diminished role of AVP in blood pressure recovery following ganglion blockade in STZ-treated rats described previously.


Asymptomatic dermatophyte scalp carriage in school children in Adana, Turkey.
The aim of this study was to determine the prevalence of asymptomatic dermatophyte scalp carriage and symptomatic tinea capitis in Adana Province, Cukurova region, Turkey. For this purpose, a screening study was performed in five schools, between January 2004 and May 2005, covering a total of 5143 children with 2740 (53.3%) boys and 2403 (46.7%) girls, aged 7-14 years (9.6 +/- 2.0). The diagnosis was made using the cotton swab method with inoculation onto Sabouraud glucose agar amended with cycloheximide, chloramphenicol and gentamicin. Among 10 (0.2%) cases, six asymptomatic carriers (mean age 10.7 +/- 2.3) and four symptomatic cases (mean age 8.3 +/- 0.5) were detected, all of whom were boys and had immigrated from the south-eastern and eastern region of Anatolia, Turkey. The mean age differences were found to be statistically significant (Mann-Whitney U=3.000, P=0.046). Boys were found to be more prone to asymptomatic carriage (P=0.033), but not tinea capitis (P>0.05). Zoophilic dermatophytes, namely Microsporum canis (40%) and Trichophyton mentagrophytes var. mentagrophytes (40%) were the most commonly isolated species, followed by anthropophilic Trichophyton tonsurans (10%), while no causative agent was detected in a case (10%) with tinea capitis superficialis. Scalp cultures were found to be dermatophyte-negative after 3- to 8-month follow-up in cases with asymptomatic carriage. As a conclusion, the prevalence of asymptomatic carrier state was similar with the prevalence of symptomatic cases, and we found a predominance of zoophilic species.


A new strategy to form multicompartment micelles: fluorocarbon-hydrocarbon ion-pair surfactant.
The hydrophobic core of the multicompartment micelles consists of incompatible and clearly separated distinct subdomains which make them different from the classical micelles. Owing to these properties multicompartment micelles have a great potential to be used as solubilization agents and carriers for a wide variety of applications where it is important to prevent the uncontrolled interaction of the solubilizates before reaching the target and to convey them to the specified point simultaneously. Here we show that effective compartmentalization inside the micelle and high solubilization capacity for the two immiscible water-insoluble materials in cases of both simultaneous and separate solubilization can be achieved by newly designed ion-pair hybrid surfactant CH(3)(CH(2))(11)(OCH(2)CH(2))(23)N(+)(C(2)H(5))(3)SO(3)(-)(CF(2))(7)CF(3) (C(12)E(23)N(+)SO(3)(-)F(8)) through the agency of favorable molecular design. Molecular structure is tailored by the approach of using a balance of forces to obtain compartmentalization, which is without precedent. This new molecule also has the properties of quite low critical micelle concentration and an extensive surfactant concentration range for solubilization which are additional important advantageous features.


Reflectivity and transmissivity of a surface covered by a disordered monolayer of large and tenuous particles: theory versus experiment.
The main objective of this paper is to endorse a recently derived theoretical model for the coherent reflectance and transmittance from a surface supporting a disordered monolayer of large and tenuous particles by comparison with experimental measurements. The model is based on the so-called anomalous-diffraction approximation and is assumed to be valid for small and moderate angles of incidence. We prepared disordered monolayers of spherical polystyrene particles of 1.8 μm diameter and of human red blood cells on glass microscope slides. In both cases, particles were immersed in a liquid of refractive index close to that of the particle. We measured the relative reflectivity and transmissivity of the samples versus the wavelength of light at normal incidence and the reflectivity and transmissivity versus the angle of incidence at a fixed wavelength, and compared with predictions of the anomalous-diffraction approximation model. For the polystyrene particle samples, we also compare the results with another available theoretical model developed some years ago to deal with disordered monolayers of highly scattering particles. In the case of red blood cell monolayers, we also present measurements with a hemolyzed sample and a disordered multilayer film for comparison. We find that the anomalous diffraction model can be fitted very well to the experimental curves, in some cases, even for high angles of incidence.


Osteostatin-coated porous titanium can improve early bone regeneration of cortical bone defects in rats.
A promising bone graft substitute is porous titanium. Porous titanium, produced by selective laser melting (SLM), can be made as a completely open porous and load-bearing scaffold that facilitates bone regeneration through osteoconduction. In this study, the bone regenerative capacity of porous titanium is improved with a coating of osteostatin, an osteoinductive peptide that consists of the 107-111 domain of the parathyroid hormone (PTH)-related protein (PTHrP), and the effects of this osteostatin coating on bone regeneration were evaluated in vitro and in vivo. SLM-produced porous titanium received an alkali-acid-heat treatment and was coated with osteostatin through soaking in a 100 nM solution for 24 h or left uncoated. Osteostatin-coated scaffolds contained ∼0.1 μg peptide/g titanium, and in vitro 81% was released within 24 h. Human periosteum-derived osteoprogenitor cells cultured on osteostatin-coated scaffolds did not induce significant changes in osteogenic (alkaline phosphatase [ALP], collagen type 1 [Col1], osteocalcin [OCN], runt-related transcription factor 2 [Runx2]), or angiogenic (vascular endothelial growth factor [VEGF]) gene expression; however, it resulted in an upregulation of osteoprotegerin (OPG) gene expression after 24 h and a lower receptor activator of nuclear factor kappa-B ligand (RankL):OPG mRNA ratio. In vivo, osteostatin-coated, porous titanium implants increased bone regeneration in critical-sized cortical bone defects (p=0.005). Bone regeneration proceeded until 12 weeks, and femurs grafted with osteostatin-coated implants and uncoated implants recovered, respectively, 66% and 53% of the original femur torque strength (97±31 and 77±53 N·mm, not significant). In conclusion, the osteostatin coating improved bone regeneration of porous titanium. This effect was initiated after a short burst release and might be related to the observed in vitro upregulation of OPG gene expression by osteostatin in osteoprogenitor cells. Long-term beneficial effects of osteostatin-coated, porous titanium implants on bone regeneration or mechanical strength were not established here and may require optimization of the pace and dose of osteostatin release.


Privacy Policy Compliance of Chronic Disease Management Apps in China: Scale Development and Content Evaluation.
With the development of mobile health (mHealth), chronic disease management apps have brought not only the possibility of reducing the burden of chronic diseases but also huge privacy risks to patients' health data. The purpose of the study was to analyze the extent to which chronic disease management apps in China comply with the Personal Information Security Specification (PI Specification). The compliance of 45 popular chronic disease management apps was evaluated from the perspective of the information life cycle. To conduct a fine-grained evaluation, a scale based on the PI Specification was developed. Finally, 6 level 1 indicators, 22 level 2 indicators, and 61 level 3 indicators were defined. There were 33/45 apps (73%) with a privacy policy, and the average score of these apps was 40.4 out of 100. Items of level 1 indicators with high scores included general characteristics (mean 51.9% [SD 28.1%]), information collection and use (mean 51.1% [SD 36.7%]), and information sharing and transfer (mean 50.3% [SD 33.5%]). Information storage and protection had the lowest compliance with PI Specification (mean 29.4% [SD 32.4%]). Few personal information (PI) controllers have stated how to handle security incidents, including security incident reporting (7/33, 21%), security incident notification (10/33, 30%), and commitment to bear corresponding legal responsibility for PI security incidents (1/33, 3%). The performance of apps in the stage of information destruction (mean 31.8% [SD 40.0%]) was poor, and only 21% (7/33) apps would notify third parties to promptly delete PI after individuals cancelled their accounts. Moreover, the scoring rate for rights of PI subjects is generally low (mean 31.2% [SD 35.5%]), especially for obtaining copies of PI (15%) and responding to requests (25%). Although most chronic disease management apps had a privacy policy, the total compliance rate of the policy content was low, especially in the stage of information storage and protection. Thus, the field has a long way to go with regard to compliance around personal privacy protection in China.


Avanafil mediated dual inhibition of IKKβ and TNFR1 in an experimental paradigm of Alzheimer's disease: in silico and in vivo approach.
In Alzheimer's disease pathology, inhibitors of nuclear factor kappa-β kinase subunit β (IKKB) and Tumor necrosis factor receptor 1 (TNFR1) signaling are linked to neuroinflammation-mediated cognitive decline. We explored the role of a phosphodiesterase 5 inhibitor (PDE5I) with dual antagonistic action on IKKB and TNFR1 to inhibit nuclear factor kappa B (NF-kB) and curb neuroinflammation. In the in silico approach, the FDA-approved Zinc 15 library was docked with IKKB and TNFR1. The top compound with dual antagonistic action on IKKB and TNFR1 was selected based on bonding and non-bonding interactions. Further, induced fit docking (IFD), molecular mechanics-generalized Born and surface area (MMGBSA), and molecular dynamic studies were carried out and evaluated. Lipopolysaccharide (LPS) administration caused a neuroinflammation-mediated cognitive decline in mice. Two doses of avanafil were administered for 28 days while LPS was administered for 10 days. Morris water maze (MWM) along with the passive avoidance test (PAT) were carried out. Concurrently brain levels of inflammatory markers, oxidative parameters, amyloid beta (Aβ), IKKB and NF-kB levels were estimated. Avanafil produced good IKKB and TNFR1 binding ability. It interacted with crucial inhibitory amino acids of IKKB and TNFR1. MD analysis predicted good stability of avanafil with TNFR1 and IKKB. Avanafil 6 mg/kg could significantly improve performance in MWM, PAT and oxidative parameters and reduce Aβ levels and inflammatory markers. As compared to avanafil 3 mg/kg, 6 mg/kg dose was found to exert better efficacy against elevated Aβ , neuroinflammatory cytokines and oxidative markers while improving behavioural parameters.Communicated by Ramaswamy H. Sarma.


The Relationship between Adults' Perceptions, Attitudes of COVID-19, Intuitive Eating, and Mindful Eating Behaviors.
In total, 1224 Turkish adults (27.5 ± 9.6 years; 80.6% female) answered sociodemographic questions, and three instruments: Mindful Eating Questionnaire (MEQ), Intuitive Eating Scale-2 (IES-2), and COVID-19 Perception and Attitude Scale. Women's perceptions and attitudes toward COVID-19 indicated higher concerns than men (p < .001). It was found that IES-2 scores of all subjects increased as body mass index (BMI) decreased and education level increased (p < .001; p = .033, respectively). During the social isolation of COVID-19, the MEQ scores of married couples and those who did not eat take-out foods were higher (p = .027; p = .006, respectively). Interestingly, it was found that as the BMI of the subjects increased, their MEQ scores increased (p < .001). The COVID-19 pandemic, which has social and economic consequences, has a great impact on human health and causes sudden lifestyle changes through social distance and isolation at home. Although social isolation during the epidemic is a necessary precaution to protect public health, the results of this study support that it causes changes in intuitive eating, and mindful eating behaviors.


Effects of phenobarbital and rose bengal on the ATPases of plasma membranes of rat and rabbit liver.
The effects of drugs which change the bile-salt-independent fraction of bile flow on Na(+)K(a+) and Mg(2+) activated ATPases were studied in membrane fractions rich in bile canaliculi. The administration of phenobarbital caused no induction of these enzymes which could explain the increased bile flow observed in the rat. Rose bengal, in addition to its strong photoxidative inhibition of both ATPases, inhibits the Na(+)K(+) ATPase of rat and rabbit bile canaliculi in the absence of light. A closely related substance, uranine, inhibits neither bile flow nor Na(+)K(+)ATPase. Inhibition of this enzyme by rose bengal may therefore be responsible for the observed effects of this dye on bile flow independent of bile salts.


Directional sensitivity of stretch reflexes and balance corrections for normal subjects in the roll and pitch planes.
A large body of evidence has been collected which describes the response parameters associated with automatic balance corrections in man to perturbations in the pitch plane. However, perturbations to human stance can be expected from multiple directions. The purpose of the present study was to describe the directional sensitivities of muscle responses re-establishing disturbed stance equilibrium in normal subjects. The contributions of stretch reflex and automatic balance-correcting responses to balance control, and concomitant biomechanical reactions, were examined for combinations of pitch and roll perturbations of the support surface. More specifically, muscle responses, initial head accelerations and trunk velocities were analyzed with the intention of identifying possible origins of directionally specific triggering signals and to examine how sensory information is used to modulate triggered balance corrections with respect to direction. Fourteen healthy adults were required to stand on a dual-axis rotating platform capable of delivering rotational perturbations with constant amplitude (7.5 degrees ) and velocity (50 degrees /s) through multiple directions in the pitch and roll planes. Each subject was randomly presented with 44 support surface rotations through 16 different directions separated by 22.5 degrees first under eyes-open, and then, for a second identical set of rotations, under eyes-closed conditions. Bilateral muscle activities from tibialis anterior, soleus, lateral quadriceps and paraspinals were recorded, averaged across direction, and areas calculated over intervals with significant bursts of activity. Trunk angular velocity and ankle torque data were averaged over intervals corresponding to significant biomechanical events. Stretch reflex (intervals of 40-100, 80-120 ms) and automatic balance-correcting responses (120-220, 240-340 ms) in the same muscle were sensitive to distinctly different directions. The directions of the maximum amplitude of balance-correcting activity in leg muscles were oriented along the pitch plane, approximately 180 degrees from the maximum amplitude of stretch responses. Ankle torques for almost all perturbation directions were also aligned along the pitch plane. Stretch reflexes in paraspinal muscles were tuned along the 45 degrees plane but at 90 degrees to automatic balance corrections and 180 degrees to unloading responses in the same muscle. Stretch reflex onsets in paraspinal muscles were observed at 60 ms, as early as those of soleus muscles. In contrast, unloading reflexes in released paraspinal muscles were observed at 40 ms for perturbations which caused roll of the trunk towards the recorded muscle. Onsets of trunk roll velocities were earlier and more rapid than those observed for pitch velocities. Trunk pitch occurred for pure roll directions but not vice versa. When considered together, early stretch and unloading of paraspinals, and concomitant roll and pitch velocities of the trunk requiring a roll-and-pitch-based hip torque strategy, bring into question previous hypotheses of an ankle-based trigger signal or ankle-based movement strategies for postural balance reactions. These findings are compatible with the hypothesis that stretch-, force- and joint-related proprioceptive receptors at the level of the trunk provide a directionally sensitive triggering mechanism underlying a, minimally, two-stage (pitch-based leg and pitch-and-roll-based trunk) balance-correcting strategy. Accelerometer recordings from the head identified large vertical linear accelerations only for pitch movements and angular roll accelerations only during roll perturbations with latencies as early as 15 ms. Thus, it appears that balance corrections in leg and trunk muscles may receive strong, receptor-dependent (otolith or vertical canal) and directionally sensitive amplitude-modulating input from vestibulospinal signals.


[2017 Census: are there enough anaesthesiologists in Portugal?]
The objective of this study is to identify the number of anaesthesiologists working in Portugal and to monitor the national activity of this medical specialty by comparing it with a similar Census performed in 2014. Observational cross-sectional study. Data related to the month of May 2017 was collected from Anaesthesiology departments of 53 Portuguese public institutions from a total of 86 hospitals. The Census registered 615 127 surgical procedures (3.4% more than in 2013), 84.1% of which on a non-emergent basis, and 49.6% day case surgery (6.1% more than in 2013). Moreover, 89 608 procedures were performed outside the operating rooms (19.0% less than in 2013), 282 944 were anaesthetic clinics (1.3% more than in 2013) and 112 183 were chronic pain evaluations (13.1% more than in 2013). In addition, 51 380 labour analgesia were performed for delivery (14.3% more than in 2013) corresponding to 70.5% of all deliveries occurring in the Obstetric department of Portuguese public hospitals in 2016 (5% more than in 2013). A total of 1280 Anaesthesiologists were identified (2.1% more than in May 2014), corresponding to a ratio of 12.4 per 100 000 inhabitants (it was 12.0 in May 2014). Together with the 262 anaesthesiologists that work exclusively in the private system, we found a total sum of 1542 anaesthesiologists indicating a ratio of 15.1 per 100 000 inhabitants (it was 13.9 in 2014). We predict that the identified deficit of 541 anaesthesiologists in the Portuguese National Health Service should be reduced by two thirds until 2023. The reduction of the shortage of anaesthesiologists will allow an increase in human resource capacity in Anaesthesiology. Even though there was a slight increase in the ratio of Anaesthesiologists per inhabitant in 2017 compared to 2014, Portugal maintains a shortage of Anaesthesiologists.


A young diabetic with suicidal risk: Rare disease with a rarer presentation.
Rare genetic or inherited forms of diabetes can mimic immune mediated type 1 diabetes. Early age of onset and associated features help to differentiate these diseases from type 1 diabetes. Wolfram syndrome, an inherited neuro degenerative disorder, presents as insulin dependent diabetes mellitus, diabetes insipidus, optic atrophy and deafness. But less well described features like psychiatric manifestations can be the presentation of this disease. We present such a case. Wolfram syndrome should be considered as a differential diagnosis in insulin dependent diabetic children who present with neuropsychiatric problems.


A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential.
Neuroendocrine (NE) cells may be involved not only in growth and differentiation of the normal prostate but also in carcinogenesis and progression of prostate adenocarcinoma (Pca), including development of androgen resistance. However, the exact pathophysiology of NE cells in Pca remains poorly understood. Here we describe a transgenic model of Pca with progressive NE differentiation. Seven lines of transgenic mice with the rat prostate-specific large probasin promoter linked to the SV40-large T antigen (Tag) that develop prostatic neoplasia have been established. In this study, one of the seven lines (12T-10) was characterized by examination of 52 mice aged from 2-12 months. With advancing age, low-grade prostatic intraepithelial neoplasia, high-grade prostatic intraepithelial neoplasia, microinvasion, invasive carcinoma, and poorly or undifferentiated carcinoma with NE differentiation appeared in the prostates in sequential order. Whereas Tag is expressed uniformly in prostate epithelium, only an increasing subset of cells in prostatic intraepithelial neoplasia showed NE differentiation by chromogranin immunostaining. Frankly invasive carcinoma developing subsequently showed occasional definitive glandular differentiation (adenocarcinoma) and particularly undifferentiated carcinoma with NE histological features similar to those observed in NE carcinomas in humans. The NE carcinomas occurred in the dorsolateral and ventral lobes and were generally androgen receptor negative. Twenty-one of 32 (66%) mice aged > or = 6 months and 15 of 17 (88%) mice aged > or = 9 months developed metastatic tumors, as confirmed by histology and/or Tag immunohistochemistry. Metastases occurred at the later time points, with metastasis to regional lymph nodes, liver, and lung being particularly common. Metastases showed histological features of NE differentiation, as confirmed by chromogranin immunostaining and electron microscopy. An athymic nude mouse that received a s.c. implant of a primary NE tumor developed Tag-positive metastatic tumors with similar NE differentiation. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry identified identical protein profiles between the primary NE tumor and lesions in the extraprostatic organs. Hence, in the 12T-10 large probasin promoter-Tag mouse, high-grade prostatic intraepithelial neoplasia develops progressively greater NE differentiation and progresses to invasive adenocarcinoma and NE carcinoma, with a high percentage of metastases. The predictable progression through these stages will allow testing of therapeutic interventions as well as possible further delineation of the role of NE cells in Pca progression.


A note on issues in meta-analysis for behavioral genetic studies using categorical phenotypes.
Meta-analysis of behavioral genetic studies would provide (i) tighter confidence intervals around parameter estimates, (ii) clarification of apparently discrepant study findings, and (iii) a mechanism for analyzing systematic causes of between-study differences. We examined some key issues that arise in the meta-analysis of categorical phenotypes. Data were simulated under a multifactorial threshold model that assumed an underlying normal liability distribution, and summary statistics (probandwise concordance rate, recurrence risk ratio, odds ratio, kappa) compared for given values of the liability correlation between relatives and given population prevalence. Although the odds ratio and kappa statistic performed well at moderate to high values of the population prevalence (15-50%), at low values all of these statistics were sensitive to overall prevalence. In cases where the assumption of a multifactorial threshold model is reasonable, direct estimation of genetic and environmental parameters from the summary statistics from all studies appears to be a preferable strategy. For cases where data from non-randomly ascertained samples are used, the impact of misspecification of the model for ascertainment was examined. For some parameter values, such misspecifications led to quite serious biases to estimates of genetic and environmental parameters. These biases varied in complex ways as a function of research design and of the true causes of variation in the population, so that the same misspecification could lead to an overestimate of the importance of genetic influences in twin data but an underestimation in adoption data or to an overestimate of the importance of genetic effects from twin data if shared environmental as well as genetic influences were simulated but an underestimate of genetic effects if shared environmental effects were assumed unimportant. These complexities emphasize the importance of being sensitive to the effects of misspecifying ascertainment corrections in any meta-analysis of behavioral genetic data.


Medical conditions of nursing home admissions.
As long-term nursing home care is likely to increase with the aging of the population, identifying chronic medical conditions is of particular interest. Although need factors have a strong impact on nursing home (NH) admission, the diseases causing these functional disabilities are lacking or unclear in the residents' file. We investigated the medical reason (primary diagnosis) of a nursing home admission with respect to the underlying disease. This study is based on two independent, descriptive and comparative studies in Belgium and was conducted at two time points (1993 and 2005) to explore the evolution over twelve years. Data from the subjects were extracted from the resident's file; additional information was requested from the general practitioner, nursing home physician or the head nurse in a face-to-face interview. In 1993 we examined 1332 residents from 19 institutions, and in 2005 691 residents from 7 institutions. The diseases at the time of admission were mapped by means of the International Classification of Diseases--9th edition (ICD-9). Longitudinal changes were assessed and compared by a chi-square test. The main chronic medical conditions associated with NH admission were dementia and stroke. Mental disorders represent 48% of all admissions, somatic disorders 43% and social/emotional problems 8%. Of the somatic disorders most frequently are mentioned diseases of the circulatory system (35%) [2/3 sequels of stroke and 1/5 heart failure], followed by diseases of the nervous system (15%) [mainly Parkinson's disease] and the musculoskeletal system (14%) [mainly osteoarthritis]. The most striking evolution from 1993 to 2005 consisted in complicated diabetes mellitus (from 4.3 to 11.4%; p < 0.0001) especially with amputations and blindness. Symptoms (functional limitations without specific disease) like dizziness, impaired vision and frailty are of relevance as an indicator of admission. Diseases like stroke, diabetes and mobility problems are only important for institutionalisation if they cause functional disability. Diabetes related complications as cause of admission increased almost three-fold between 1993 and 2005.


Structural alterations and inflammation in the heart after multiple trauma followed by reamed versus non-reamed femoral nailing.
Approximately 30,000 patients with blunt cardiac trauma are recorded each year in the United States. Blunt cardiac injuries after trauma are associated with a longer hospital stay and a poor overall outcome. Organ damage after trauma is linked to increased systemic release of pro-inflammatory cytokines and damage-associated molecular patterns. However, the interplay between polytrauma and local cardiac injury is unclear. Additionally, the impact of surgical intervention on this process is currently unknown. This study aimed to determine local cardiac immunological and structural alterations after multiple trauma. Furthermore, the impact of the chosen fracture stabilization strategy (reamed versus non-reamed femoral nailing) on cardiac alterations was studied. 15 male pigs were either exposed to multiple trauma (blunt chest trauma, laparotomy, liver laceration, femur fracture and haemorrhagic shock) or sham conditions. Blood samples as well as cardiac tissue were analysed 4 h and 6 h after trauma. Additionally, murine HL-1 cells were exposed to a defined polytrauma-cocktail, mimicking the pro-inflammatory conditions after multiple trauma in vitro. After multiple trauma, cardiac structural changes were observed in the left ventricle. More specifically, alterations in the alpha-actinin and desmin protein expression were found. Cardiac structural alterations were accompanied by enhanced local nitrosative stress, increased local inflammation and elevated systemic levels of the high-mobility group box 1 protein. Furthermore, cardiac alterations were observed predominantly in pigs that were treated by non-reamed intramedullary reaming. The polytrauma-cocktail impaired the viability of HL-1 cells in vitro, which was accompanied by a release of troponin I and HFABP. Multiple trauma induced cardiac structural alterations in vivo, which might contribute to the development of early myocardial damage (EMD). This study also revealed that reamed femoral nailing (reamed) is associated with more prominent immunological cardiac alterations compared to nailing without reaming (non-reamed). This suggests that the choice of the initial fracture treatment strategy might be crucial for the overall outcome as well as for any post-traumatic cardiac consequences.


SlicerDMRI: Open Source Diffusion MRI Software for Brain Cancer Research.
Diffusion MRI (dMRI) is the only noninvasive method for mapping white matter connections in the brain. We describe SlicerDMRI, a software suite that enables visualization and analysis of dMRI for neuroscientific studies and patient-specific anatomic assessment. SlicerDMRI has been successfully applied in multiple studies of the human brain in health and disease, and here, we especially focus on its cancer research applications. As an extension module of the 3D Slicer medical image computing platform, the SlicerDMRI suite enables dMRI analysis in a clinically relevant multimodal imaging workflow. Core SlicerDMRI functionality includes diffusion tensor estimation, white matter tractography with single and multi-fiber models, and dMRI quantification. SlicerDMRI supports clinical DICOM and research file formats, is open-source and cross-platform, and can be installed as an extension to 3D Slicer (www.slicer.org). More information, videos, tutorials, and sample data are available at dmri.slicer.org Cancer Res; 77(21); e101-3. ©2017 AACR.


Effectiveness of Technologically Enhanced Peer Support in Improving Glycemic Management Among Predominantly African American, Low-Income Adults With Diabetes.
The purpose of the study was to examine whether a peer coaching intervention is more effective in improving clinical outcomes in diabetes when enhanced with e-health educational tools than peer coaching alone. The effectiveness of peer coaches who used an individually tailored, interactive, web-based tool (iDecide) was compared with peer coaches with no access to the tool. Two hundred and ninety Veterans Affairs patients with A1C ≥8.0% received a 6-month intervention with an initial session with a fellow patient trained to be a peer coach, followed by weekly phone calls to discuss behavioral goals. Participants were randomized to coaches who used iDecide or coaches who used nontailored educational materials at the initial session. Outcomes were A1C (primary), blood pressure, and diabetes social support (secondary) at 6 and 12 months. Two hundred and fifty-five participants (88%) completed 6-month and 237 (82%) 12-month follow-up. Ninety-eight percent were men, and 63% were African American. Participants in both groups improved A1C values (>-0.6%, P < .001) at 6 months and maintained these gains at 12-month follow-up ( >-0.5%, P < .005). Diabetes social support was improved at both 6 and 12 months ( P < .01). There were no changes in blood pressure. Clinical gains achieved through a volunteer peer coach program were not increased by the addition of a tailored e-health educational tool.


ECHDC3 variant regulates the right hippocampal microstructural integrity and verbal memory in type 2 diabetes mellitus.
ECHDC3 is a risk gene for white matter (WM) hyperintensity and is associated with insulin resistance. This study aimed to investigate whether ECHDC3 variants selectively regulate brain WM microstructures and episodic memory in patients with type 2 diabetes mellitus (T2DM). We enrolled 106 patients with T2DM and 111 healthy controls. A voxel-wise general linear model was employed to explore the interaction effect between ECHDC3 rs11257311 polymorphism and T2DM diagnosis on fractional anisotropy (FA). A linear modulated mediation analysis was conducted to examine the potential of FA value to mediate the influence of T2DM on episodic memory in an ECHDC3-dependent manner. We observed a noteworthy interaction between genotype and diagnosis on FA in the right inferior temporal WM, right anterior limb of the internal capsule, right frontal WM, and the right hippocampus. Modulated mediation analysis revealed a significant ECHDC3 modulation on the T2DM → right hippocampal FA → short-term memory pathway, with only rs11257311 G risk homozygote demonstrating significant mediation effect. Together, our findings provide evidence of ECHDC3 modulating the effect of T2DM on right hippocampal microstructural impairment and short-term memory decline, which might be a neuro-mechanism for T2DM related episodic memory impairment.


Effects of pentoxifylline on hemodynamic, hemorheological, and microcirculatory parameters in young SHRs during arterial hypertension development.
The most common form of hypertension in young adults is isolated diastolic hypertension. Diastolic arterial pressure is determined by the total peripheral resistance and depends on both vascular hindrance and blood viscosity. The aim of our work was to study the efficiency of pentoxifylline (PTX) in young spontaneously hypertensive rats (SHRs) during the development of arterial hypertension. The effects of a treatment course with PTX (100 mg/kg/day p.o. for 6 weeks, from 5 to 11 weeks old) on the mean, systolic, and diastolic blood pressure (BP); stroke volume; cardiac output; total peripheral resistance (TPR); whole blood viscosity (BV); plasma viscosity; hematocrit; RBC aggregation and deformability; local cerebral blood flow (lCBF); and microvascularization of the visual cortex were studied in SHRs in comparison with control SHRs and Wistar Kyoto rats. PTX-treated SHRs had significantly lower systolic, diastolic, and mean BP (by 24%, 26%, and 15%, respectively) and BV (by 5-9%) and a higher erythrocyte deformability index (by 1.5-2%), lCBF (by 42%), average diameter of capillaries (by 11%), density of the capillary network (by 23%), and percentage of capillaries with a diameter of 3-7 µm in comparison with control SHRs. In conclusion, PTX exerted positive effects on the hemodynamic, hemorheological, and microcirculatory parameters in SHRs during the development of arterial hypertension.


Intra-hepatic arterial drug delivery.
In this review, the pharmacokinetic rationale for hepatic arterial drug therapy is discussed, along with techniques that have been developed in order to try to enhance the regional advantage accrued from this route of administration. Clinical trials of hepatic arterial therapy in patients with primary hepatocellular carcinoma and with liver metastases from colorectal carcinoma are discussed. Although clinical response rates are significantly better with regional as compared with systemic therapy, survival is not prolonged. This is mainly due to the development of extrahepatic metastases. A treatment strategy using high dose hepatic arterial 5-fluorouracil (5-FU) infusion with the deliberate aim of achieving maximum tolerated systemic drug levels has entered phase III clinical trial. Monitoring of in vivo tumour pharmacokinetics using 19F magnetic resonance spectroscopy and 18F-5-FU positron emission tomography (PET) demonstrate elegantly how target drug uptake may be assessed. We plan to use PET to monitor intra-tumoral viral transduction and 5-flucytosine conversion rates to active 5-FU in our hepatic arterial pro-drug gene therapy programme soon to enter clinical trial.


Micro-Computed Tomography Analysis of Fit of Ceramic Inlays Produced with Different CAD Software Programs.
The aim of this study was to evaluate marginal and internal fit of ceramic inlays designed with different computer-aided design software programs. 11 typodont mandibular first molars were prepared as a ceramic class II mesioocclusal inlay cavity. Teeth were scanned using 3Shape TRIOS Intraoral Dental Scanner. The scan data, which was obtained in the form of a STL file, was designed in three different CAD systems (CEREC, KaVo, and Planmeca). The obtained STL scan data was exported to design inlay using three different CAD systems (CEREC, KaVo, and Planmeca). An independent 5-axis milling unit was used to manufacture the feldspatic inlay restorations. 11 measurements for each teeth were made by using micro-ct to evaluate the marginal and internal fit. One-way ANOVA was used to determine the statistical difference between groups, and Tukey posthoc test was used to determine intra-group differences. According to repeated ANOVA test results, a statistically significant difference was found between the groups for the variables A, D, and F. There was no statistically significant difference between the groups in linear measurements for other measurement points and volumetric measurements (p⟩0.05). Software programs of different systems affects the marginal and internal fit of inlay restorations.